The noncoding RNAs SNORD50A and SNORD50B bind K-Ras and are recurrently deleted in human cancer

Z Siprashvili, DE Webster, D Johnston, RM Shenoy… - Nature …, 2016 - nature.com
Z Siprashvili, DE Webster, D Johnston, RM Shenoy, AJ Ungewickell, A Bhaduri, R Flockhart…
Nature genetics, 2016nature.com
Small nucleolar RNAs (snoRNAs) are conserved noncoding RNAs best studied as
ribonucleoprotein (RNP) guides in RNA modification,. To explore their role in cancer, we
compared 5,473 tumor-normal genome pairs to identify snoRNAs with frequent copy number
loss. The SNORD50A-SNORD50B snoRNA locus was deleted in 10–40% of 12 common
cancers, where its loss was associated with reduced survival. A human protein microarray
screen identified direct SNORD50A and SNORD50B RNA binding to K-Ras. Loss of …
Abstract
Small nucleolar RNAs (snoRNAs) are conserved noncoding RNAs best studied as ribonucleoprotein (RNP) guides in RNA modification,. To explore their role in cancer, we compared 5,473 tumor-normal genome pairs to identify snoRNAs with frequent copy number loss. The SNORD50A-SNORD50B snoRNA locus was deleted in 10–40% of 12 common cancers, where its loss was associated with reduced survival. A human protein microarray screen identified direct SNORD50A and SNORD50B RNA binding to K-Ras. Loss of SNORD50A and SNORD50B increased the amount of GTP-bound, active K-Ras and hyperactivated Ras-ERK1/ERK2 signaling. Loss of these snoRNAs also increased binding by farnesyltransferase to K-Ras and increased K-Ras prenylation, suggesting that KRAS mutation might synergize with SNORD50A and SNORD50B loss in cancer. In agreement with this hypothesis, CRISPR-mediated deletion of SNORD50A and SNORD50B in KRAS-mutant tumor cells enhanced tumorigenesis, and SNORD50A and SNORD50B deletion and oncogenic KRAS mutation co-occurred significantly in multiple human tumor types. SNORD50A and SNORD50B snoRNAs thus directly bind and inhibit K-Ras and are recurrently deleted in human cancer.
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